Neoplastic diseases are recognized throughout the world as being serious and often life-threatening conditions. These neoplastic diseases have been and continue to be the subject of worldwide research efforts directed toward the identification of therapeutic agents which are effective in the treatment of patients suffering therefrom.
There are a variety of anti-tumor agents to treat neoplastic diseases. For example, 5-fluorouracil (hereinafter referred to as “5-FU”) is an antimetabolite having a structure of pyrimidine analog, which is used as a drug in the treatment of neoplastic diseases. Its principal uses are in gastrointestinal cancer such as gastric cancer, colon cancer, rectal cancer and pancreatic cancer. Other uses are for example, in hepatic cancer, breast cancer, uterine cancer and ovarian cancer. The chemotherapy agent 5-FU acts principally as a thymidylate synthase inhibitor. Thymidylate synthase inhibitors include 5-FU, Capecitabine, Tegafur, Carmofur, Floxuridine, and so on. Tegafur is known to release 5-FU when activated in the living body. 5-FU is known to have the serious problem that the prolonged presence of 5-FU in the living body causes damages in the digestive organs such as oral cavity and intestine. Patients receiving continuous intravenous infusion of 5-FU alone often experience those damages.
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum(II) (CDDP) is a platinum-based chemotherapy drug used to treat various types of cancers, including testicular tumor, bladder cancer, prostatic cancer, ovarian cancer, non-small cell lung cancer, esophageal carcinoma, cervical cancer, gastric cancer, osteosarcoma, lymphomas, and germ cell tumors. It was the first member of a class of anti-cancer drugs which now also includes carboplatin, nedaplatin and oxaliplatin. These platinum complexes react in vivo, bind to and cause crosslinking of DNA which ultimately triggers apoptosis (programmed cell death).
In general, severe side effects of those anti-tumor agents limit the dose escalation and prevent from achieving higher therapeutic effects.
In order to improve the therapeutic effect, some combinations of plural drugs which have different mechanisms and different side effects are proposed. However, more potent drugs and therapeutic method are still strongly desired such that the survival time of cancer patients is further prolonged and that the QOL of cancer patients is improved.
Prostaglandins (hereinafter, referred to as PG(s)) are fatty acid derivatives, members of class of organic carboxylic acids, which are contained in tissues or organs of human or other mammals, and exhibit a wide range of physiological activity. PGs found in nature (primary PGs) generally have a prostanoic acid skeleton as shown in the formula (A):

On the other hand, some of synthetic analogues of primary PGs have modified skeletons. The primary PGs are classified into PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs according to the structure of the five-membered ring moiety, and further classified into the following three types by the number and position of the unsaturated bond at the carbon chain moiety:
Subscript 1: 13,14-unsaturated-15-OH
Subscript 2: 5,6- and 13,14-diunsaturated-15-OH
Subscript 3: 5,6-, 13,14-, and 17,18-triunsaturated-15-OH.
Further, the PGFs are classified, according to the configuration of the hydroxyl group at the 9-position, into α type (the hydroxyl group is of an α-configuration) and β type (the hydroxyl group is of a β-configuration).
PGs are known to have various pharmacological and physiological activities, for example, vasodilatation, inducing of inflammation, platelet aggregation, stimulating uterine muscle, stimulating intestinal muscle, anti-ulcer effect and the like.
Some 15-keto (i.e., having oxo at the 15-position instead of hydroxy)-PGs and 13,14-dihydro (i.e., having single bond between the 13 and 14-position)-15-keto-PGs are fatty acid derivatives known as the substances naturally produced by the action of enzymes during the metabolism of primary PGs.
U.S. Patent application publication No. 2006/0281818 to Ueno et al. describes that a specific prostaglandin compound has a significant effect on a conformational change in the TJs that results in recovery of gastrointestinal mucosal barrier function.